Changed the description of ZS to sodium zirconium cyclosilicate. Increased the number of subjects in the randomized withdrawal study from 120 to 200 subjects due to a US FDA request for a less sensitive power analysis. Removed the testing for fasting plasma glucose since fasting serum glucose was collected at the same time points. Modified the dose stopping rule to include the Acute Phase and changed the upper limit of the i-STAT potassium value that required discontinuation of study drug from 6.4 to 7.0 mmol/L to mirror the upper limit that was used in the recently completed Phase 3 study, ZS-003. Added details regarding the analysis of data from the randomized withdrawal study.

Reduced the i-STAT potassium value requiring a dose increase of ZS to 5 g QD or 10 gQD from 5.6 to 7.0 mmol/L to 5.1 to 7.0 mmol/L. Reduced the i-STAT potassium value that required discontinuation of study drug in the randomized withdrawal study from > 7.0 mmol/L to > 6.2 mmol/L, which was consistent with the completed study, ZS-004, which had a placebo arm. Limited participation in the randomized withdrawal study to selected sites in North America rather than all study sites. Clarified that the site was to contact the Medical Monitor for dosing directions in the rare case that the i-STAT potassium value was between 3.0 to 3.4 mmol/L during the Acute Phase. Updated animal toxicity data from a 9-month oral toxicity study in dogs to support dosing in man beyond 9 months. Removed the requirement that a person who was reading a consent form to a vision-impaired non-English speaking subject be a member of the research team who was fluent in the language of the subject since it was not always possible to have members of the research team fluent in multiple languages. In most cases, study sites had access to individuals who were not members of the study team who could read the consent to the subject in the subject’s primary language and translate information between the subject and the investigator. Clarified that only sexually active women of childbearing potential were to use 2 forms of medically acceptable contraception with at least 1 being a barrier method. Removed the lower limit for room temperature storage of study drug based on ongoing stability data.

Reduced the i-STAT potassium value that required a subject to stop dosing in the Extended Dosing Phase from > 7.0 mmol/L to > 6.5 mmol/L for increased safety during long-term dosing. Required subjects to return to the site 7 (± 1) days later if a RAAS inhibitor or diuretic dose was adjusted or initiated during the Extended Dosing Phase or randomized withdrawal study to measure potassium since changes in either of these medications may have altered the level of blood potassium. The i-STAT potassium value was to be evaluated, and the dose of ZS was adjusted or stopped based on the rules in the protocol. Clarified that all Extended Dosing Phase visits from Day 8 onwards may have taken place either 1 day early or 1 day late to provide greater flexibility with scheduling. Removed the requirement for the randomized withdrawal study to start when the first subject on Extended Dosing Phase Day 176 met the criteria for entry in the randomized withdrawal study. Changed the lower limit of age of an eligible subject from 19 to 18 years of age. Added the collection of blood samples for analysis of zirconium at baseline and on the morning of Acute Phase Day 2 as recommended by the US FDA at selected study sites in North America. Added additional sampling time points for the collection of blood for aldosterone and renin on Extended Dosing Phase Days 29 and 267. Modified secondary and exploratory endpoints and a secondary objective. Removed information from nonclinical studies that was available in the Investigator’s Brochure. Deleted the collection of urine for p-cresol and indole at all time points and deleted the collection of blood for BNP and galectin-3 at all time points except baseline (Acute Phase Day 1)

Increased the enrollment in the Extended Dosing Phase from 500 to 750 subjects to allow sites in Europe sufficient opportunity to enroll subjects in the study. Allowed the Medical Monitor to request a dose adjustment based on the central laboratory potassium value and not the i-STAT value if there was a significant discrepancy between the values. This was to be determined on a case-by-case basis by the Medical Monitor. Dose escalation was still only requested if central laboratory S-K value was > 5.0 mmol/L (increase from 5 g QOD to 5 g QD or increase from 5 to 10 g QD) or > 5.5 mmol/L (increase from 10 to 15 g QD). Defined medically acceptable contraception as requested by the Clinical Trials Facilitation Group in the European Union as part of the Voluntary Harmonization Procedure assessment.

Added clarification of medically acceptable contraception methods to Inclusion Criterion 5.

Incorporated the use of a lower volume of water (40 mL with no mandatory rinses) to deliver the study drug for subjects who enrolled in the trial under this amendment at selected sites in the US. All other subjects were to continue to use 180 mL plus 2 mandatory rinses of 30 mL each to deliver the study drug. This allowed for the collection of safety and tolerability data of the study drug using a lower volume of water. Subjects who enrolled in the study under this amendment at selected sites in the US received a dosing card that provided detailed written directions for proper preparation of study drug doses. If a subject who should have consumed ZS using 40 mL of water with no mandatory rinses mistakenly used 180 mL of water followed by two 30 mL rinses, this was to be recorded on the subject’s dosing card and in EDC as a deviation and accounted for during data analysis. Added 2 new secondary endpoints and modified an exploratory endpoint. Incorporated all country-specific wording, thereby eliminating the need for any country-specific amendments. Specified that expected progression of CKD requiring dialysis, transplant or other treatment resulting in study discontinuation was not to be reported as an adverse event in this trial. The event was to be reported on the End of Study eCRF in EDC. Removed the requirement that the independent Data Monitoring Committee (iDMC). review data on an ongoing basis for this study. The ZS Pharma Medical Monitor continued to monitor safety data throughout the study.

Removed the randomized withdrawal study from the trial. Emerging data from ZS-005 consistently showed that once treatment was stopped (on Day 365), S-K values returned into the hyperkalemic range. In addition, interim data from Study ZS-005 very clearly demonstrated that ZS maintained normokalemia in 90 to 100% of the subjects with a mean S-K value of 4.6 mmol/L. Changed the title of the protocol due to removal of the randomized withdrawal study from the trial. Clarified that subjects who had a history of heart failure were classified according to the New York Heart Association functional classification system. Clarified that adverse events were collected for 7 (± 1) days after the last dose of study drug which corresponded with the acceptable time frame of the End of Study visit. Clarified that expected progression of CKD requiring dialysis, transplant, or other treatment resulting in study discontinuation not related to ZS was not to be reported as an adverse event or serious adverse event.